Clinical depression is a debilitating mood disorder with a lifetime prevalence rate of 15-20% and a mortality rate of up to 20%. Current antidepressant drug treatments, all of which target monoaminergic systems in the brain, require several weeks of treatment before the onset of efficacy, and induce remission in only half of patients. Although the mechanism of antidepressant action is poorly understood, it has recently been suggested that antidepressant-induced neurogenesis may underlie clinical response. In order to test this hypothesis, and to determine whether the response to antidepressants has a genetic component, we propose to quantitate adult hippocampal cell proliferation and apoptosis in twenty inbred strains of mice with or without chronic antidepressant treatment. These phenotypes will be used for haplotype mapping, a type of quantitative trait locus analysis, in order to identify candidate genes regulating aspects of both basal and antidepressant-induced neurogenesis. We will then measure the performance of control and antidepressant-treated mice 'on the tail suspension test, a measure of behavioral despair, to determine whether the magnitude of the behavioral response to antidepressants is associated with the extent to which antidepressants affect neurogenesis. PUBLIC HEALTH RELEVANCE: The primary goals of the proposed experiments are: a) to identify genes that regulate the production of new neurons during adulthood, b) to identify genes associated with the behavioral and neurogenic response to antidepressants, and c) to determine whether antidepressants may affect behavior via the regulation of neurogenesis. The results will help us to better understand the ultimate mechanism by which antidepressants provide relief from depression.